Wednesday, 13 December 2017

As you may know, we at Barts-MS are passionate about the importance of upper limb function for people with MS. And our#ThinkHandcampaign aims to increase awareness.Part of this project is to develop a new way for people to record and measure their upper limb function. We currently work with Patient Reported Outcome Measures (PROMs), such as the ABILHAND, which is a questionnaire that patients are asked to complete at clinical visits. Read more about that in a previous blog post.

Monday, 11 December 2017

We were grateful when a number of readers responded to our enquiry regarding temperature dependent symptoms in MS, and we learned more about how people cope with the symptoms. Following this conversation, I thought it worthwhile to draw attention to a paper we recently published, that suggests that there are functional differences between normal peripheral and central axons, and these differences provide a new view on temperature sensitivity.

Saturday, 9 December 2017

As you may be aware I have been banging on about the importance of B memory cells for most of the year, but it has been an uphill struggle to get this view accepted. However, response to therapy creates a powerful piece of insight that frankly can't be ignored. But I meet Ostriches ever day.

Friday, 8 December 2017

ProfG G has been been saying that we should #Thinkhand and target hand function for outcomes in clinical trials. This idea may be supported by studies with ocrelizumab and natalizumab but there are a couple of exceptions.

Thursday, 7 December 2017

I have just returned from the European Charcot Foundation meeting in Baveno, Italy. The meeting is small (< 500 attendees) with no parallel sessions and ample time to mix with attendees and chew the cud. I did a plenary presentation on "dealing with increasing economic constraints". The feedback I received after my talk, and subsequently via email, has been extraordinary. An eminent neurologist said he was glad that someone was thinking about these issues and taking it on. I have also been contacted by a health economist and have been urged to write up the talk.

Monday, 4 December 2017

It has been a while since I last wrote a post for this blog and figured it was time to update you all! I have recently completed my training with Professor Giovannoni and it really confirmed my desire to pursue a career in MS. I am back home in Colombia just getting ready to finish my residency in Neurology. I am incredibly grateful for the time I spent with the Barts and The London Neuroimmunology Group. Every member of the team was very passionate about MS and brought that excitement to teach me. I am delighted to be able to keep in touch with you all through this blog. Please enjoy my new post and don't forget to leave your comments below!

Sunday, 3 December 2017

The mechanisms which drive inflammation and neuron death in MS are very complicated. These processes involve interactions between multiple cell types in and outside the brain. The crosstalk between nerve cells (neurons), immune cells from the blood, and brain-resident supporting cells (glia) is important to study because it could open up new avenues for disease-modifying therapy.

Although oligoclonal bands in the cerebrospinal fluid have been a hallmark of multiple sclerosis diagnosis for over three decades, the role of antibody-secreting cells in multiple sclerosis remains unclear. T and B cells are critical for multiple sclerosis pathogenesis, but increasing evidence suggests that plasma cells also contribute, through secretion of autoantibodies. Long-lived plasma cells are known to drive various chronic inflammatory conditions as e.g. systemic lupus erythematosus, however, to what extent they are present in autoimmune central nervous system inflammation has not yet been investigated. (Who are they kidding...oh yes the referees) In brain biopsies from multiple sclerosis patients and other neurological diseases, we could detect non-proliferating plasma cells (CD138+Ki67-) in the parenchyma. Based on this finding, we hypothesized that long-lived plasma cells can persist in the central nervous system (CNS). In order to test this hypothesis, we adapted the multiple sclerosis mouse model experimental autoimmune encephalomyelitis to generate a B cell memory response. Plasma cells were found in the meninges and the parenchyma of the inflamed spinal cord, surrounded by tissue areas resembling survival niches for these cells, characterized by an up-regulation of chemokines (CXCL12), adhesion molecules (VCAM-1) and survival factors (APRIL and BAFF). In order to determine the lifetime of plasma cells in the chronically inflamed CNS, we labeled the DNA of proliferating cells with 5-ethynyl-2'-deoxyuridine (EdU). Up to five weeks later, we could detect EdU+ long-lived plasma cells in the murine (mouse) CNS. To our knowledge, this is the first study describing non-proliferating plasma cells directly in the target tissue of a chronic inflammation in humans, as well as the first evidence demonstrating the ability of plasma cells to persist in the CNS, and the ability of the chronically inflamed CNS tissue to promote this persistence. Hence, our results suggest that the CNS provides survival niches for long-lived plasma cells, similar to the niches found in other organs. Targeting these cells in the CNS offers new perspectives for treatment of chronic autoimmune neuroinflammatory diseases, especially in patients who do not respond to conventional therapies.

Plasma cells which produce antibody are often found in bone marrow and can live for years but you put them in cell culture and they are dead in a few days. This is because the cells survive in niches where they recieve survival factors from surrounding cells. In this study they track the presence of plasma cells over weeks in animals and suggest that plasma ells survive for some time. I guess we have thought this happens for some time and it is evident that many of the plasma cells in the CNS are not directed to myelin antigens.

The question is what are we going to do?

Have a read if you are interestedThe problem here ,is the pictures show the random isolated plasma cell and not B cell follcles

CONCLUSION:

Amiloride has not demonstrated any neuroprotective benefit within this trial paradigm, but future neuroprotective trials in ON should target the window of opportunity to maximise potential neuroprotective benefit.

Data from Brain SeqAmiloride is blocker of ASICS1 channel. This is a neuronal voltage-insensitive sodium channel activated by extracellular protons permeable to Na+, however ASIC1 also shows low Ca2+permeability. It was shown to be neuroprotective in animal models so of we go and do a trial and as we can see as occurred here...the trial fails and animals studies take a beating, like so many other studies.

However I have been arguing that animal studies are not always the problem. I am sorry to say clinicians conspire to mess things up. Sorry but it bursts my bubbles too.

In this study people who had optic neuritis had a month to get on drug. But this is too late as the damage has been done. The damage is done within a few days as we showed in animals, which led to a positive trial when people were recruited and put on treatment within 1-2 weeks as shown in

However, this has chucked away our animal data as this trial was not followed up to change practice such that people with optic neuritis get treated with phenytoin. However I think the amiloride has another problem as it made the nerve transmission slower suggesting that it block remyelination.

It is interesting that oligodendrocyte presusor cells have loads of ion channels on them and this includes ASIC1 (ACCN2) and this drops once cells produce myelin. See the picture. So is this chnnel involved in myelination

If you have a question unrelated to the Posts this is the place for you. In the past we have done an advent calendar in December, to advertise the Research Day.However, we do not know about the planning of this, So the mice are off on tour.

Wednesday, 29 November 2017

As you see we are trying to post less often on the blog so that you have more time to read and discuss the posts. The following blog post is a bit of a cheat as I have reviewed three papers. However, they are all related to coffee and are relevant to pwMS and their families.

Are you addicted to coffee? If you are, don't worry, the latest research suggests it may be good for you. However, if you have urinary symptoms, anxiety, tremor or sleep problems there may be a downside.

Monday, 27 November 2017

Tony Blair is famously quoted as saying 'Education, education, education, ...' and putting education at the centre of New Labour's manifesto in 1997. However, is it the type or the quality of education that makes the difference and changes the world?

Thursday, 23 November 2017

We have recently reached out to a number of young carer organisations across the country, encouraging them to hold a Digesting Science event (the Barts-MS set of activities explaining MS to 6-12 year olds). Recently, we got some great feedback from the South Tyneside Young Carers, and thought we'd share their fantastic work with you. Post by Levi Cosker, South Tyneside Young Carers Activity Officer.

Sunday, 19 November 2017

A recent study published in the British Medical Journal (BMJ) proposes a simple three talk model for shared-decision making in the clinic. Have you been involved in a shared-decision making process, or have you simply been told what is best for you?Please have your say.

We don’t understand yet why people get MS. The accepted view is that there is an interaction between risk genes and environmental factors like EBV, smoking, and vitamin D status. Epidemiological studieshave helped to identify these risk factors for developing MS, but it is unclear how these factors actually contribute to disease evolution and progression.

Wednesday, 15 November 2017

"Low dose naltrexone (LDN) has become a popular off-label therapy for multiple sclerosis (MS). A few small, randomized studies indicate that LDN may have beneficial effects in MS and other autoimmune diseases. If proven efficacious, it would be a cheap and safe alternative to the expensive treatments currently recommended for MS. We investigated whether a sudden increase in LDN use in Norway in 2013 was followed by changes in dispensing of other medications used to treat MS."

Tuesday, 14 November 2017

More and more HSCT procedures (aka bone marrow transplants) are being performed for MS around the world than ever before. Currently, we lack convincing data on the conditioning regimen that best balances efficacy and safety. Patient selection is key and HSCT should be considered as an early option in aggressive cases of inflammatory MS, rather than as salvage therapy in later disease.

Monday, 13 November 2017

Translocator protein (TSPO) is found on the outer mitochondrial membrane (in other words, on the outside of the powerhouse of the cell). It is thought to be involved in regulation of several cellular processes but its actual function is still up for debate.

Sunday, 12 November 2017

Any type of injury to the brain - whether focal or diffuse - can increase your risk of developing epileptic seizures. pwMS who have lots of lesions or significant atrophy are probably more at risk of developing epilepsy. The exact risk of epilepsy in MS has been a bit variable in reported studies. Because the absolute numbers of pwMS who also develop epilepsy is quite low, you need a really big cohort to see if there is any increased risk compared to people without MS.

Saturday, 11 November 2017

Bio: RAH is a Norwegian MD, currently a PhD candidate in the MS section of the Clinical Neuroscience group at Akershus University Hospital. Previous work includes examining the many effects of glatiramer acetate on the immune system. Our current work is focusing on B cells in particular, and their potential pathological collaboration with T cells in pwMS.

Although this won't make me popular with the "imagers", here you have it from the horse's mouth "magnetic resonance imaging alone provides limited information for predicting an individual patient's disability progression".

Wednesday, 8 November 2017

At #MSParis207 I presented a new analysis of the data of the ASCEND trial (natalizumab in SPMS) that shows natalizumab is very effective in protecting upper limb function, and to a lesser extent lower limb function, in people with more advanced MS (majority needing walking aids).

Sunday, 5 November 2017

You may be aware that people living with MS in resource-poor environments are often not treated with disease-modifying therapies. To address this we have been promoting a Barts-MS Essential Off-label list of DMTs. The problem with this list is that it is often not backed by a so-called 'class 1 evidence'. To address this lack of evidence, trials such as COMBAT-MS are being performed to provide data from real-life practice to support off-label prescribing. We are therefore privileged to have a guest post from the team running the COMBAT-MS trial explaining what the trial is about.

Friday, 3 November 2017

Fingolimod is an effective DMT which binds to the sphingosine-1-phosphate receptor on white blood cells. We don’t fully understand why it works in MS, but the most popular theory is that it traps lymphocytes inside the lymph nodes, preventing them from entering the blood and therefore from penetrating into the CNS. It may also have direct anti-inflammatory effects, protect the integrity of the blood-brain barrier, and (possibly) act directly in the CNS as a neuroprotective agent.

This afternoon Mouse Doctor and Neuro Doc Gnanapavan broadcast live from the MS Paris ECTRIMS ACTRIMS conference for a one hour Google Hangout. This was your opportunity to listen to the summary of what they've seen but also respond to questions posted by readers of this blog.

Tuesday, 24 October 2017

The Programme (UK)/Program (US) is online (CLICK HERE) The abstracts are now live

Come and see us at the Google Hangout 15.45-16.45 Central European Summer Time = GMT + 2 h) with NDG and ProfB your hosts to answer your questions and to report on what's "Hot" and What's "Not"....OK, they won't waste their time, and your time, with the what's not :-).If you miss the Hangout some of us can be found on the ClinicSpeak and DigestingScience stands.

The Barts MS team will go to ECTRIMS this week with a spring in our step. On Saturday night, we attended the Zenith Global Healthcare awards and won a Team Recognition award. Not only this, but Professor Giovannoni was awarded with a Lifetime achievement award.

Monday, 23 October 2017

You may have seen this BBC news article today about two pwMS. One of which had a well-planned trip to Switzerland to end his life. After meeting a local woman with MS he appears to have a new outlook and has postponed his trip to Switzerland indefinitely.

Friday, 20 October 2017

There are few things that all MSologists agree on. Perhaps one of the least controversial statements you can make about MS is that it is a disease of the Central Nervous System - i.e. the brain, brainstem, cerebellum, and spinal cord - and that it does not affect the peripheral nerves.Plus ca change.

Monday, 16 October 2017

In just over a week, MS researchers, Nurses and Clinicians will travel to Paris for the annual ECTRIMS conference. This is an important meeting where new research, trial results and treatment information is shared across the community. And we'd like some input from you, our readers!

Saturday, 14 October 2017

Neutrophils are your first line of defence against infection, but they express CD52 and therefore they are depleted by alemtuzumab. This will contribute to infections post treatment, but, whilst common, the level of depletion is rarely severe and long-lasting. We have commented on this in a previous post, but you can now get a free copy of the paper.

Wednesday, 11 October 2017

Is the term ‘progressive MS’ a misnomer? In general, progression means improvement, not worsening. We have made the case for using the term ‘advanced MS’, which we think captures the disability that comes with the later stages of MS.

As you know I have been moaning about the Late Breaking abstracts selection at ECTRIMS2017, yep sour grapes:-(...as our paper wasn't selected for a talk:-( We will report on how and why cladribine works Luckily (for them) our cladribine poster on effects on lymphocytes is not next to the company sponsored poster. Wonder what they will say? But as my alemtuzumab poster in next to it, I'll get hear:-).But as for the rest of the late breakers we have many where the results are announced, so if you are pressed for time you can get home early.1. We have the Fingolimod trial in children.....It worked (CLICK HERE)2. We have anti retro virus trial...It failed at 6 months (CLICK HERE) but then it worked at 6 months (CLICK HERE)

5.We have pathogenic antibodies to MOG, which we are not sure if this is that important to all or only a subset of MS

6. Looking forward to the MS sprint progressive trial but no announcement from Medicinova...except that enrollment was completed in Sept and results expected 2018 (CLICK). But then they say "Dr. Fox will present the top line safety, tolerability and efficacy data of ibudilast in progressive MS".

7. Then there was the last one imaging lymphatics in primates, I thought who is interested in monkey brains?

Anyway we don't have to wait for ECTRIMS and glad to see that humans are imaged and so it is clear we have drainpipes from the brain. These will take stuff into the lymph glands.

Absinta M, Ha SK, Nair G, Sati P, Luciano NJ, Palisoc M, Louveau A, Zaghloul KA, Pittaluga S, Kipnis J, Reich DS. Human and nonhuman primate meninges harbor lymphatic vessels that can be visualized noninvasively by MRI. Elife. 2017 Oct 3;6. pii: e29738. doi: 10.7554/eLife.29738.Here, we report the existence of meningeal lymphatic vessels in human and nonhuman primates (common marmoset monkeys) and the feasibility of noninvasively imaging and mapping them in vivo with high-resolution, clinical MRI. On T2-FLAIR and T1-weighted black-blood imaging, lymphatic vessels enhance with gadobutrol, a gadolinium-based contrast agent with high propensity to extravasate across a permeable capillary endothelial barrier, but not with gadofosveset, a blood-pool contrast agent (Gadofosveset binds reversibly to serum albumin, increasing its molecular weight from 0.9 to 67 kDa. Under physiological conditions, albumin has a low transcapillary exchange rate into the interstitial compartment, estimated to be on the order of 5% per hour, which explains the propensity of gadofosveset to remain within blood vessels). The topography of these vessels, running alongside dural venous sinuses, recapitulates the meningeal lymphatic system of rodents. In primates, meningeal lymphatics display a typical panel of lymphatic endothelial markers by immunohistochemistry. This discovery holds promise for better understanding the normal physiology of lymphatic drainage from the central nervous system and potential aberrations in neurological diseases.

So we know that there is lymphatic type drainage in rodents and the presence of glymphatics and not it is evident that there are drainage pathways from the brain. It means that proteins can move from the brain to the node.

If you are interested in reading the brain drainage system has been known for some time, so you can even read about the glymphaticsHowever in the study they could not prove whether lymphatic vessels drain immune cells, CSF, or other substances from the brain to deep cervical lymph nodes, nor could we assess any link with the glymphatic system

There is a neat video if you follow the link to the paper, so the next question is where does the spinal cord drain to? I suppose I can ask this at ECTRIMS2017 in a couple of weeks

Multiple sclerosis (MS) is the leading cause of chronic neurological disability in young adults. The clinical disease course of MS varies greatly between individuals, with some patients progressing much more rapidly than others, making prognosis almost impossible. We previously discovered that cytotoxic CD4+ T cells (CD4+ CTL), identified by the loss of CD28, are able to migrate to sites of inflammation and that they contribute to tissue damage. Furthermore, in an animal model for MS, we showed that these cells are correlated with inflammation, demyelination, and disability. Therefore, we hypothesize that CD4+ CTL drive progression of MS and have prognostic value. To support this hypothesis, we investigated whether CD4+ CTL are correlated with worse clinical outcome and evaluated the prognostic value of these cells in MS. To this end, the percentage of CD4+CD28null T cells was measured in the blood of 176 patients with relapsing-remitting MS (=baseline). Multimodal evoked potentials (EP) combining information on motoric, visual, and somatosensoric EP, as well as Kurtzke expanded disability status scale (EDSS) were used as outcome measurements at baseline and after 3 and 5 years. The baseline CD4+CD28null T cell percentage is associated with EP (P = 0.003, R2 = 0.28), indicating a link between these cells and disease severity. In addition, the baseline CD4+CD28null T cell percentage has a prognostic value since it is associated with EP after 3 years (P = 0.005, R2 = 0.29) and with EP and EDSS after 5 years (P = 0.008, R2 = 0.42 and P = 0.003, R2 = 0.27). To the best of our knowledge, this study provides the first direct link between the presence of CD4+ CTL and MS disease severity, as well as its prognostic value. Therefore, we further elaborate on two important research perspectives: 1° investigating strategies to block or reverse pathways in the formation of these cells resulting in new treatments that slow down MS disease progression, 2° including immunophenotyping in prediction modeling studies to aim for personalized medicine.Yesterday, we had yet another post on the memory B cells and we had some cracking questions., some of which I could only give a "I don't really know yet" answer but we have been asking the same questions....but the answers need a bit more thought and a lot more reading.

But we need to ask questions and there is a killer punch we need to kill the idea and reformulate it we find the idea is wrong.

We need to listen to alternatives and here is another one. This study suggests that MS is cause by CD4 T cell that are killing machines and that they too occur in loads of different diseases.

You can read the paper as it is open access. They are expanded CD4+CD28null T cells are found in about 20% of both pwMS as well as healthy controls without obvious differences in numbers.

They are suggested to that these cells link to progression.

I would counter this by saying:

(a) CD4 T cell depletion does not stop progression at least quickly

(b) CD4 deletion does not work in MS

(c) Histologically there are few CD4 T cells in lesions, there are few in the nervous tissue

(d) Oligodendrocytes do not express MHC classs II, which is a recognition element targeted by CD4 T cells

(e) Then we ask does the data pass the "smack you in the eye test" and are the R2 values big enough, to me it says the effects cannot be explained by the CD4 T cells.

They do address the issue of CD4 monoclonal antibody and intimate that the level of depletion wasn't big enough. We have also suggested that it may have been on the brink of not being enough based on animal studies, but alemtuzumab knocks CD4 and CD8 cells to pieces and this does not stop advanced MS. So the argument probably falls.

Saturday, 7 October 2017

#UnderstandingyourtreatmentsspeakWe have been making the case that memory B cells are a central player in the treatment target for all drugs in MS. As we saw yesterday many people don't buy this idea (see below) or perhaps don't even know about this idea because they: (a) don't read the blog; (b) Don't read papers (c) cannot assimilate knowledge or (d) all of the above:-) or (e) I'm wrong.Yesterday I was sad, because it confirmed what I wrote above.So I want to put more meat on the ideaI was talking about B cells and the fact there were are more than one type of cell that make up the CD19 population.Some didn't like my slide

You (at least one of you) said I was talking "jibberish" and it is unrelated to people with MS and it was more relevant to scientists and doctors.I said "nonsense" because, it is important in understanding the choices that you may need to make.Is the level pitched wrongly...the answer will be yes and perhaps no...however virtually every part of the post has been explained in the past and so look at the education posts to help you get up to speed.If you look at alemtuzumab, the CD19 B cell population (in green below) is back to normal levels within 3 months. But alemtuzumab is still working years later...so it can't be the B cell? Can it?

This is the view if you see CD19 B cells as a single population as is usually portrayed. So can it be the B cell?Yes it can, because that repopulation is occurring because of immature and then mature (also called naive B cells) cell subsets come rushing out of the bone marrow to fill the space vacated by the lymphocytes that are killed. This masks the fact that memory B cells are being depleted long-term.

See our picture from Baker et al. 2017 (below). This is the pattern you see with rituximab, and HSCT so there is nothing special going on.

The blue (Total CD19+) is a composite response of the (green, pink and the baby blue). The antibody is given at 0 and 12 months and shows percentage change from baseline (-80 = 80% depletion)

This is the default pathway for B cell repopulation and will occur for all drugs that kill B cells. However, with HSCT and alemtuzumab, this occurs in the relative absence of effective T cell regulation by CD8 T cells and maybe CD4 T regs. The default pathway of T cells is the immediate repopulation comes from expansion of the memory cells, this is seen in humans and mice. There is nothing special going on.

Alemtuzumab is a humanized monoclonal antibody approved for the treatment of relapsing-remitting multiple sclerosis (RRMS), given as two annual courses on five consecutive days at baseline and on three consecutive days 12 months later. Here we provide an update on the long-term efficacy and safety of alemtuzumab in RRMS, including real-world experience, and advances in our understanding of its mechanism of action. Recent data from the phase II/III extension study have demonstrated that alemtuzumab reduces relapse rates, disability worsening, and the rate of brain volume loss over the long term, with many patients achieving no evidence of disease activity. In high proportions of patients, pre-existing disability remained stable or improved. Alemtuzumab is associated with a consistent safety profile over the long term, with no new safety signals emerging and the overall annual incidence of reported adverse events decreasing after the first year on treatment. Acyclovir prophylaxis reduces herpetic infections, and monitoring has been shown to mitigate the risk of autoimmune adverse events, allowing early detection and overall effective management. Data from clinical practice and ongoing observational studies are providing additional information on the real-world use of alemtuzumab. Recent evidence on the mechanism of action of alemtuzumab indicates that in addition to its previously known effects of inducing depletion and repopulation of T and B lymphocytes, it also results in a relative increase of cells with memory and regulatory phenotypes and a decrease in cells with a proinflammatory signature, and may further promote an immunoregulatory environment through an impact on other innate immune cells (e.g. dendritic cells) that play a role in MS. These effects may allow preservation of innate immunity and immunosurveillance. Together, these lines of evidence help explain the durable clinical efficacy of alemtuzumab, in the absence of continuous treatment, in patients with RRMS.

This is a review and we don't report of reviews but it is perhaps good that you can get an alternative view. If you can get access to this.

However I have been spending the day getting my poster ready for ECTRIMS 2017 and so was happy to see the state of play, but....reading through this makes me feel that I am am living in an alternative universe:-(.

Apparently there are "no new safety signals" emerging so best not give a plug for the ECTRIMS poster that shows alemtuzumab can stop working

P1231. C. Eggers, K. Akgün, T. Hofer, M. Egger, T. Ziemssen

Abrogation of the lymphocyte depleting action of Alemtuzumab by neutralizing antibodies - a case report.

Apparently there is "recent evidence on the mechanism of action of alemtuzumab" so I thought great...our ideas are gaining some traction....but then the depression sets in.

So in addition to the mechanism of inducing depletion and repopulation of T and B lymphocytes ,we get a result in a relative increase of cells with memory and regulatory phenotypes...yeah that's T cells. I guess memory B are not on the radar yet.

So the 30,000 cells per millilitre going down to 2 is still an increase in the minds of my peers?. Maybe that the 2 Treg cells are now controlling the 1 surviving CD4 T cell is the relative cell increase we need.

The new mechanism is a expansion of NKCD56 high, so it works like daclizumab too?

So if we do reviews, should we regurgitate a string of facts or try and tease mechanisms from the literature...I prefer the latter but maybe I am in a minority....too much speculation. What do you think?Come back tomorrow. I'll have a go.

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General Disclaimer: Please note that the opinions expressed here are those of the individual bloggers and do not necessarily reflect the positions of the Barts and The London School of Medicine and Dentistry, Queen Mary University of London or Barts Health NHS Trust.

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